Skin care composition with retinyl ester as vitamin a propionate retinyl palmitate d-alpha tocopherol rice amino acids and liposomes and method of application

ABSTRACT

A skin conditioning composition combining specific percentages of a retinyl ester as vitamin A propionate, retinyl palmitate, vitamin E as d-alpha tocopherol, with rice amino acids and liposomes to create an efficient vehicle for skin rejuvenation without common complications of typical retinoid therapy. Also discloses is a method of application.

BACKGROUND OF THE INVENTION

[0001] It is well known that retinol and retinyl esters enhancekeratinocyte proliferation and the synergistic inhibition ofkeratinocyte differentiation. Retinoic acid has been shown to be mosteffective in producing these results which reduce the occurrance ofacne. However, substantial irritation and erythema can occur atsufficient strengths to produce therapeutic results. Recent use ofretinoids has suggested treatment for photoaging and sun damage.Examples of this are characteristic wrinkling, loss of elasticity,roughened texture and hyperpigmentation. U.S. Pat. No. 6,080,393 to Liu,et al. addresses the preference of certain retinyl esters, retinol andretinal as preferred forms in formulating skin care compositions withthese naturally occurring retinoids.

[0002] Delivering stable vitamin A in therapeutic strengths forreduction of photoaging and improvement of skin texture without sideeffects has been problematic. Fulton, Jr. addresses this in U.S. Pat.No. 5,043,356. He states that vitamin A propionate has clinicallydemonstrated unexpectedly superior properties for the treatment of skindisorders with markedly reduced side effects. Dermal alterationsresulting from excessive sun exposure can be corrected with anaccompanying improvement in the skin appearance. The molecular weight ofvitamin A propionate, which is an ester of retinol and propionic acid,is the correct molecular weight and configuration to remain in a stablesolution and to be transdermally delivered while it is active.

[0003] Increasing strengths of vitamin A propionate can increase thetherapeutic benefits of retinoic treatment, but in increasingproportions, the typical side effects of retinoid therapy still occur,such as increased surface tension, irritation, dry, scaling anderythema.

[0004] When increasing retinyl ester strength for more therapeuticvalue, it has been found that surface irritation can be decreased byameliorating the less desirable side effects with larger moleculeretinyl palmitate and d-alpha tocopherol in combinations so that theratio of the palmitate/tocopherol mixture remains constant.

SUMMARY OF THE INVENTION

[0005] The problems of the prior art have been overcome by the presentinvention, which provides a cosmetic preparation shown to significantlyenhance skin quality without substantial irritation, and a method ofapplying the preparation to the skin. The compositions of the presentinvention include a therapeutically effective amount of a retinyl esteras vitamin A propionate that minimizes or eliminates the side effectscommonly associated with vitamin A. An optimal formula for addressingphotoaging of skin contains percentages of a retinyl ester as vitamin Apropionate at 4.5%-6.0%.

[0006] For amelioration of possible side effects, several additionalcomponents can be used in the invention. Because retinoid compounds canbe unstable, an oil-in-water emulsion is the preferred formula. Whenusing an oil-in-water emulsion along with an antioxidant, the retinoidcomposition remains fairly stable. The larger molecule of retinylpalmitate and d-alpha tocopherol tend to remain at surface levels forsoftening side effects of irritation and erythema. Additionally, theyprovide antioxidant benefit and increase surface humidity, therebyaiding in delivery through the stratum corneum. Because the stratumcorneum is the first rate-limiting membrane of the epidermis, thecondition of the skin affects the actual percutanious absorption.Hydrated skin increases percutaneous absorption potential (E M Jackson,Percutaneous absorption: scientific basis for new products or concernfor safety, presented at the 38^(th) International CIDESCO Conference,New York, N.Y. (Aug. 20, 1984). The amount of retinyl palmitate andd-alpha tocopherol found to be most beneficial is a constant ratio of1:1:1 to that of vitamin A propionate.

[0007] In its method aspects, the present invention relates to thetopical application to the skin of a patient a formulation containing atherapeutically effective amount of vitamin A proprionate, together withvitamin A palmitate and d-alpha tocopherol, most preferably in about a1:1:1 weight ratio.

DETAILED DESCRIPTION OF THE INVENTION

[0008] A predominant emulsion type is the oil-in-water emulsion, wherethe dispersed phase is oil and the surrounding phase is water. The oiland water are held together by applying physical energy and usingchemical emulsifiers, which have hydrophilic and lipophilic ends to bindboth the oil and water (Zatz, Joel L., Skin Permeation Fundamentals andAppication, Wheaton, Ill., Allured Publishing, 1993). Percutaneousabsorption is governed by the principles of passive diffusion. Thestratum corneum controls percutaneous absorption to a greater degreethan the other rate-limiting barriers of the skin. The reciprocalfunction of the stratum corneum is also its reservoir function. Thisfunction allows concentrations of the retinyl ester to remain in thestratum corneum as concentration of the permeant decreases with eachsuccessive epidermal stratum.

[0009] Liposomes act as a delivery agent in the preparation. Liposomalformulations, when topically applied, exhibit unique propertiesbeneficial to a wide variety of cosmetic applications. They encapsulatehigh concentrations of water and lipid soluble substances and facilitatetheir delivery into the skin. Liposomes are microscopic vesiclescomposed of one or more lipid bilayers arranged in concentric fashionenclosing an equal number of aqueous compartments. (A D Bangham, M MStandish and J C Watkins, the action of steroids and steptolysin S onthe permeability of phospholipid structures to cations, J Mol Biol 13138 (1965)). When mixed at high speeds, they encapsulate the vitamin Apalmitate and d-alpha tocopherol. Vegetable phospholipids are widelyused for topical applications in cosmetics and dermatology since theyhave a high content of esterfied essential fatty acids, especiallylinoleic acid. (M M Rieger, Skin lipids and their importance to cosmeticscience, Cosm & Toil 102 36 (1987); H Lautenschlager, J. Roding and M.Ghyczy, The use of liposomes from soya phospholipids in cosmetics, SOFW14 531 (1988)). Liposomal deposition into the stratum corneum results ina substantial reservoir effect. A skin lipid formula containingceramides, cholesterol, palmitic acid and cholesteryl sulfate in theweight ratio of 4:2.5:2.5:1 can be used by preparing with a conventionalfilm method. In a study reported by Egbaria, Weiner, the uptake anddistribution of retinoic acid in the deeper skin strata at 24 hours wasgenerally 3-4 times higher from liposomal formulations than fromsolutions or emulsions (K. Egbaria, C. Ramachandran and N. Weiner,Topical application of liposomally entrapped ciclosporin evaluated byin-vitro diffusion studies with human skin, Skin Pharmacol 4 21 (1991)).

[0010] Rice protein as rice amino acids have been shown to aid in skinfirmness, moisturization and to increase microcirculation. A productsuch as by trade name, Aqua Pro II by Midwest Grain, at 1.0% to 5.0% informulation can decrease substantial irritation while aiding in theprimary objective of firmness.

[0011] Suitable thickening agents can be chosen from cellulosicderivatives such as hydroxyethyl cellulose, methyl cellulose,carboxymethylcellulose and sodium carboxlymethylhydroxyethylcellulose.They may also be chosen from natural gums or starches such as guar,carrageenum or rice starch.

[0012] Additional moisturizing agents and solvents may be utilized forpreparation of phases, such as propylene glycol. Other oils may beutilized, as an example, rice bran oil, which contains ferulic acid andphytic acid known as food preservative, antioxidant, stabilizing andchelating.

[0013] The compositions of the present invention can be prepared bymixing or blending procedures known to those skilled in the art.Preferably the aqueous phase is prepared by weighing the appropriateamount of water and mixing in the cellulose until uniform. The mixtureis heated to about 70-75° C., and is then cooled to about 40° C.Preferably the oil phase is prepared by mixing the appropriate amountsof oil (e.g., castor oil), vitamin A propionate, retinyl palmitate andd-alpha tocopherolin a suitable vessel at a temperature of about 65° C.This mixture is then cooled to about 35° C. Methyl and propylene glycol,for example, are added to the aqueous mixture, mixed, and the oilmixture is then added under agitation. Liposomes, such as BioBotanicals, are then added and mixed at high speed, and the resultingformulation is allowed to settle.

[0014] Frequency of use can depend upon factors including the skin typeand skin condition of the patient, patient age, and the climate. Thefollowing application procedure is preferred, with exceptions for age,climate and skin type noted accordingly:

[0015] Morning Procedure

[0016] For the morning procedure usage of the composition of the presentinvention is the same for all skin types, ages, and climates. Patientswith sensitive skin or rosacea should use the inventive compositionevery other morning for the first 2 to 3 weeks. After 2 to 3 weeks, theyshould start using the composition every morning, as the skin'stolerance of the composition will increase over time.

[0017] There are four simple steps in the morning:

[0018] Step 1: Before cleansing, apply Enzyme, especially under the eyesand all over the face. The Enzyme has the following composition: ITEMSSHARED (By Weight) Distilled Water  39% Cranberry-Resveratrol Complex 40% 1-Glucoronic 11.5%  1-Lactic Acid 3.8% Rye Polyglucose 4.2% JasmineOil 1.5%

[0019] Care must be taken not to get any Enzyme in the eye. The Enzymeis left on for approximately 3 to 5 minutes. If sensitivity orirritation occurs, reduce the time the Enzyme is left on the skin.Immediately remove the Enzyme by showering or rinsing the skin. TheEnzyme helps remove dead skin.

[0020] Step 2: Follow with the Cleanser using a washcloth with warmwater. The Cleanser has the following composition: ITEMS SHARED (ByWeight) Demineralized Water  43% TEA Lauryl Sulfate  15% CocamidopropylBetaine  13% Oleamide D.E.A. 4.07%  Aloe Vera 7.5% Glycerine 4.85%  SageExtract 1.2% Cucumber Extract  .6% Lactic Acid 4.5% Green Tea Extract1.5% Tea Tree Oil   2% Citric Acid .04% Salicylic Acid  .9% Polysorbate20 .03% Sodium Ascorbate .06% Vitamin E Acetate .05% Glycerin .22%Methylchlorisothazolinone .55% Methylisothiazolinone .08% Methylparaben.03% Propylparaben  .8% Fragrance .02%

[0021] After cleansing, use warm water with a washcloth and soak yourskin for 2 to 3 minutes. Make sure to soak (more than rub) the skin.Skin irritation may occur if the skin is rubbed too aggressively.

[0022] Step 3: Using the forefinger, apply 1 pump of the skin carecomposition of the invention under each eye by laying it close to thelower eyelashes. Let the composition absorb into the eye area. Do notrub. Rubbing will spread the product away from your eye area. Continueby applying 4 to 6 pumps of the composition all over the face. Do notrub. Wait 5 minutes for the composition to absorb.

[0023] Step 4: After the composition has absorbed apply Therapy Gel as amoisturizer and sunscreen over the composition. The Therapy Gel has thefollowing composition: ITEMS SHARED (By Weight) Deionized Water  32%Aloe Vera  22% Propylene Glycol  12% Shea Butter 8.5% Sunflower FattyAcids   5% Allantoin 2.3% Beeswax 1.5% Ceresin 1.5% d-alpha tocopherol2.85%  Cellulose   2% Cucumber Oil   1% Calendula Extract  .9% Citroen.45% Zinc Oxide   3% Titanium Dioxide   5%

[0024] Night Procedure

[0025] For the night procedure usage of the inventive composition variesaccording to skin types, ages and climates and consists of 2 programs. Aspecial note: all patients must begin with Program 1 for the first 2weeks to gradually build the skin's tolerance to the product.

[0026] Program 1: Recommended for Colder, Dryer Climates, Ages Under 30,Sensitive Skin or Rosacea.

[0027] This program does not use the skin care composition of theinvention at night. Cleanse with the Cleanser using a washcloth. Aftercleansing, soak your skin with warm water for 3 to 4 minutes. ApplyTherapy Gel every night and leave on. Do not apply the Enzyme at night.

[0028] After 2 weeks if you are over 30, have normal to oily skin and donot live in a colder dryer climate you may proceed to Program 2.

[0029] Program 2: Recommended for Ages Over 30, Normal to Oily Skin andMost Climates.

[0030] This program uses the product every other night in addition to inthe morning. Cleanse with the Cleanser using a washcloth. Aftercleansing, soak your skin with warm water for 2 to 3 minutes. The firstnight, apply the product (see Step 3 under Morning Procedure). Followwith Therapy Gel over the product. The second night apply only TherapyGel and leave on. Continue to alternate first and second nightprocedures (using the product every other night.) Do not apply theenzyme at night.

[0031] The inventive composition may be applied 2 times per week on theneck area.

EXAMPLE 1

[0032] In patients clinically observed for use of product the followinghas been reported:

[0033] In a total of 40 patients who have used a topically appliedformula with about 6.0% vitamin A propionate, retinyl palmitate andd-alpha tocopherol

[0034] 10 patients have been able to use the formula one time per daytopically applied with no significant irritation

[0035] 23 patients have been able to use the formula two to four timesper week with no significant irritation

[0036] 6 patients have been able to use the formula one to two times perweek with no significant irritation

[0037] 1 patient used the formula one time per week or less with nosignificant irritation

[0038] All patients reported some visible change after use of productfor a period of six weeks or longer. Self-reporting claims are smoother,tighter skin and less visible lines.

EXAMPLE 2

[0039] A focus group utilizing a formulation of the invention in a serumof the following composition was executed: Distilled water: 56%  CastorOil: 14%  Methyl glycol: 9% Vitamin A propionate: 6% Vitamin Apalmitate: 6% d-alpha tocopherol: 6% Cellulose: 5% Rice amino acids: 4%Liposomes: 1%

[0040] The purpose of the group trial was to substantiate and validatecosmetic claims concerning benefits and usage of the product. It was aself-evaluating and self-reporting group.

[0041] All participants followed the defined instructions of applicationwhich include frequency of use and which are integral to the results ofthe product claims:

[0042] All participants agreed to compliancy and used only the followingproducts on their skin:

[0043] Serum—a retinyl ester serum with the following composition: ITEMSSHARED (By Weight) Distilled Water 59%  Castor Oil 14%  Methyl Glycol 9%Vitamin A Propionate 6% Vitamin A Palmitale / d-alpha tocopherol 6%Liposomes 1% Cellulose 5%

[0044] Cleanser—a mild cleanser of gel consistency, suitable for anyskin type, with the composition shown above

[0045] Therapy Gel—a gel cream consistency moisture product, with thecomposition as shown above

[0046] The Cleanser and the Therapy Gel product were given as a controlto replace the cleansing and moisture products that the participantnormally would have been using.

[0047] All participants had the same application method and instructionsand used the products for a period of six weeks.

[0048] A.M. Instructions for Every Day of Trial:

[0049] 1. Use warm water and wash cloth to soak skin, applyapproximately 2 ml. of cleanser to face and cleanse. Rinse again withwarm water. Apply warm water in compress form with cloth for about 2minutes before drying with towel.

[0050] 2. Apply a total of 5 metered pumps of serum to entire face andunder eye area (0.3 ml metered pump dose). Allow to absorb. Do not applyto eye lids.

[0051] 3. Apply moisture gel in light application over entire area.

[0052] P.M. Instructions for Weeks 1 and 2:

[0053] 1. Follow step 1 of A.M. instructions for cleansing.

[0054] 2. Follow step 3 of A.M. instructions for moisture.

[0055] P.M. Instructions for Weeks 3, 4 and 5:

[0056] 1. Follow step 1 of A.M. instructions for cleansing.

[0057] 2. Follow step 2 of A.M. instructions for serum application.Apply every other night only.

[0058] 3. Follow step 3 of A.M. instructions for moisture.

[0059] A technician evaluation prior to start of program and at the endof the six-week trial, along with before and after pictures, were usedas a base line reference.

[0060] Of 15 people who participated in the study, 7 fell in the definedparameters for age category, which was 35 -54. These participants ofStudy One had a variety of normal to dry skin types. Their FitzPatrickscale values ranged from I-III, with light to moderatehyperpigmentation. Of these participants, 6 out of 7 (85.5%) reportedsome improvement in one week. All participants (100%) reported moderateto strong improvement in at least 4 of the defined categories at the endof 6 weeks. No participants reported dry, irritable skin with anyerythema, conditions typically associated with retinoid therapy. Oneparticipant reported an acne break out at 3 weeks. No erythema orirritation was noted by technician.

[0061] The results of the self-reported categories for Study One are inTable A and Table B. TABLE A Study One Condition S % M % N % Fine Lines1 14% 6 86% 0 0% Wrinkles 1 14% 4 57% 2 29% Smoothness 1 14% 6 86% 0 0%Firmness 1 14% 5 71% 1 14% Texture 1 14% 6 86% 0 0% Discoloration 1 14%2 28% 4 57%

[0062] TABLE B Study One Participants Reporting ConditionModerate-Strong Improvement in Six Weeks Fine Lines 100% Wrinkles  71%Smoothness 100% Firmness  85% Texture 100% Discoloration  42%

[0063] The study was repeated with an additional 8 participants who didnot fall within the defined age parameters. These participants had avariety of normal, oily and dry skin types. Their FitzPatrick scalevaried from I-III. They had light to moderate hyperpigmentation noted.

[0064] Of this group, Study Two, 7 out of 8 (87.5%) reported someimprovement in the first week. Six out of 8 (75%) reported strong tomoderate improvement in at least 4 of the defined categories at the endof 6 weeks. One participant reported light itching as a complication.One participant reported an acne break out at one week. No participantsreported dry skin or erythema, conditions typically associated withretinoid therapy. No erythema or irritation was noted by the technician.

[0065] The results of the self reported group Study Two are in Table Cand Table D. TABLE C Study Two Condition S % M % N % Fine Lines 4 40% 337.5% 1 12.5% Wrinkles 3 37.5% 2 25% 3 37.5% Smoothness 5 62.5% 3 37.5%0  0% Firmness 5 62.5% 1 12.5% 2 25% Texture 4 50% 2 25% 2 25%Discoloration 1 12.5% 2 25% 5 62.5%

[0066] TABLE D Study Two Participants Reporting Condition Moderate toStrong Improvement in Six Weeks Fine Lines 87.5% Wrinkles 62.5%Smoothness  100% Firmness   75% Texture   75% Discoloration 37.5%

[0067] In conclusion, 86.5% of all participants reported someimprovement in the first week of use. At the end of six weeks, in anaverage of both studies, participants reported a moderate to strongimprovement in: Fine Lines 93.5% Wrinkles 66.8% Skin Smoothness  100%Firmness   80% Texture 87.5% Hyperpigmentation 52.3%

[0068] Reported complications were 13% reporting an increase in acnebreak out in weeks 1 -3, which resolved by week 6. Also reported was oneparticipant (6%) with itching, which resolved by week 6 with noadditional treatment.

[0069] It is significant to report that the category with the leastchange was improvement in discoloration (hyperpigmentation), although achange of over 52% improvement was noted. It is also significant that100% of participants reported an improvement in skin smoothness.Smoothness was defined by participants as a tactile improvement inoverall softness and moisture with no apparent areas of dry skin. It isalso significant to report a total improvement of 93.5% in finewrinkles, which was defined by participants as lines around the eyearea.

What is claimed is:
 1. A topically applied composition for treatingphotoaging and skin regeneration without substantial irritation of acosmetically acceptable vehicle in an oil in water emulsion comprising:from about 4.1% to about 8 by weight retinyl palmitate; from about 4.1%to about 8.0% by weight d-alpha tocopherol; and from about 4.1% to about8.0% by weight vitamin A propionate.
 2. The composition of claim 1wherein said product has a pH of about 4.8


6. 3. The composition of claim 1 wherein the proportion of retinylpalmitate to d-alpha tocopherol remains equal.
 4. The composition ofclaim 1, further comprising a thickener selected from the groupconsisting of hydroxyethyl cellulose, natural gums, guar, carrageenumand rice starch.
 5. The composition of claim 1, further comprisingacceptabl a moisturizing agent.
 6. The composition of claim 1, furthercomprising oil.
 7. The composition of claim 1, further comprisingpropylene gylcol.
 8. The composition of claim 1, wherein the ratio ofretinyl palmitate, d-alpha tocopherol and vitamin A proprionate is about1:1:1.
 9. The composition of claim 1, further comprising: from about0.1% to 5.0% by weight rice amino acids; from about 0.1% -5.0%acceptable thickner; from about 0.5% to 1.0% liposomes; and from about50.0% to 90.0% water.
 10. A method of condition the skin of a patient,comprising: providing a composition comprising: from about 4.1% to about6.0% by weight retinyl palmitate; from about 4.1% to about 6.0% byweight d-alpha tocopherol; and from about 4.1% to about 6.0% by weightvitamin A propionate; and topcially applying said composition to theskin of said patient.
 11. The method of claim 10, wherein saidcomposition further comprises: from about 0.1% to 5.0% by weight riceamino acids; from about 0.1% -5.0% acceptable thickner; from about 0.5%to 1.0% liposomes; and from about 50.0% to 90.0% water.
 12. The methodof claim 10, wherein said retinyl palmitate, d-alpha tocopherol andvitamin A propionate are present in a weight ratio of about 1:1:1.